Cell death is an important aspect during the embryonic or post-natal development of major organ systems. Apoptosis, or programmed cell death, also plays a critical role in maintaining homeostasis in many adult tissues. Apoptosis is a term used to refer to the process(es) of programmed cell death and has been described in several cell types (Waring et al. (1991) Med. Res. Rev. 11: 219; Williams GT (1991) Cell 65: 1097; Williams GT (1992) Trends Cell Biol. 2: 263; Yonisch-Rouach et al. (1991) Nature 352: 345). Apoptosis is likely involved in controlling the amount and distribution of certain differentiated cell types, such as lymphocytes and other cells of the hematopoietic lineage as well as other somatic and germ cells. The mechanism(s) by which apoptosis is produced in cells is incompletely understood, as are the regulatory pathways by which the induction of apoptosis occurs.
Apoptosis Mechanism(s)
Apoptosis was first described as a morphologic pattern of cell death characterized by cell shrinkage, membrane blebbing and chromatin condensation culminating in cell fragmentation (Kerr et al., 1972). One hallmark pattern early in the process of cell death is internucleosomal DNA cleavage (Wyllie, 1980). The death-sparing effects of interrupting RNA and protein synthesis and the stereotyped patterns of cell death during development were consistent with a cell autonomous genetic program for cell death (Wyllie et al. (1980) Int. Rev. Cytol. 68: 251; Sulston, J. and Horvitz, H. (1977) Develop. Biol. 56: 110; Abrams et al. (1993) Development 117: 29). The isolation of mutants defective for developmental cell death in the nematode Caenorhabditis elegans supported this view (Ellis, H. and Horvitz, H. (1986) Cell 44: 817; Hengartner et al. (1992) Nature 356: 494). Control of apoptosis may be a regulatory feature of a variety of diseases, such as aging, AIDS, and autoimmune diseases, among others. Despite the identification of genes necessary for cell death and the ability to regulate apoptosis by known genes, the essential biochemical events in apoptotic death remain largely unknown.
Cell Proliferation Control and Neoplasia
Many pathological conditions result, at least in part, from aberrant control of cell proliferation, differentiation, and/or apoptosis. For example, neoplasia is characterized by a clonally derived cell population which has a diminished capacity for responding to normal cell proliferation control signals. Oncogenic transformation of cells leads to a number of changes in cellular metabolism, physiology, and morphology. One characteristic alteration of oncogenically transformed cells is a loss of responsiveness to constraints on cell proliferation and differentiation normally imposed by the appropriate expression of cell growth regulatory genes. Despite progress in developing a more defined model of the molecular mechanisms underlying the transformed phenotype and neoplasia, few significant therapeutic methods applicable to treating cancer beyond conventional chemotherapy have resulted.
Thus, it is desirable to identify agents which can modify apoptosis activity so as to modulate cell proliferation, differentiation, and/or apoptosis for therapeutic or prophylactic benefit. Further, such agents can serve as commercial research reagents for control of cell proliferation, differentiation, and/or apoptosis in experimental applications, and/or for controlled proliferation and differentiation of predetermined stem cell populations in vitro, in ex vivo therapy, or in vivo.
A variety of neurodegenerative diseases are characterized by cell death of neurons by a mechanism that is not presently distinguishable from many known models of apoptosis. Some of these neurodegenerative diseases appear to be related to excess accumulation of certain proteins. Examples of such amyloidosis-related neurodegenerative diseases include those caused by the prion protein (PrP) which is associated with transmissible spongiform encephalopathy (Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, scrapic, and kuru), and those caused by excess cystatin C accumulation (hereditary cystatin C angiopathy), among others. Although much current effort is being expended on certain neuronal diseases associated with senile dementia, there is less effort being devoted to neurodegenerative diseases which are related to excess accumulation of certain proteins other than the A.beta. peptide.
It would be desirable to have compounds and methods or treating non-Alzheimer's type neurodegenerative diseases wherein neuron loss is produced by apoptotic cell death which can be circumvented by suitable therapeutic intervention with pharmaceuticals.
There is a need in the art for pharmaceuticals which have therapeutic use to treat or prevent such apoptosis-related neurodegenerative diseases which have similar pathogenic mechanisms. A more thorough understanding of the molecular events underlying the development and progression of such neurodegenerative diseases would facilitate development of such pharmaceuticals. Identification of critical biochemical events involved in these apoptosis-related neurodegenerative diseases can provide a basis for development of methods and model systems for screening compound banks to identify such pharmaceuticals, as well as providing a basis for the design of therapeutic methods and treatment modalities for neurodegenerative disease.
It would be desirable to have methods and model systems for screening test compounds for the ability to inhibit or prevent or inhibit neuronal toxicity produced by neurotoxic agents which induce neuronal apoptosis. In particular, it would be desirable to base such methods and systems on metabolic pathways and/or signal transduction pathways which have been found to be involved in such pathogenesis, where the test compound would be able to interrupt or interfere with the metabolic pathway or signal transduction pathway which leads to damage of neuronal and/or glial cells in the presence of a pathogenic apoptotic stimulus. Such methods and systems should provide rapid, economical, and suitable means for screening large numbers of test compounds.
Based on the foregoing, it is clear that a need exists for identification of metabolic pathways and/or signal transduction pathways which have been found to be involved in the pathogenesis of apoptosis-related neurodegenerative diseases, and the development of methods of treatment and pharmaceutical screening assays based on the identification of these pathways. The present invention fulfills these and other needs in the art.
The references discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.